Search bioRxiv⌕ Search

bioRxiv · 10.1101/303628

Comparative analysis of IgG Responses to recombinant Qβ phage displayed MSP3 and UB05 in Dual HIV-malaria infected adults living in areas differing in Malaria transmission intensities

Abstract

Immunoglobulin G specific responses against Plasmodium falciparum merozoite antigens such as the merozoite surface protein 3 (MSP3) and UB05 are known to play critical roles in parasitemia control and protection from symptomatic illness. However when there is intense perennial malaria transmission coupled with concurrent infection with the human immunodeficiency virus type 1 (HIV), knowledge of IgG antibody response profiles is limited. In this study we assessed the impact of dual HIV-Malaria infections on IgG subclass responses to MSP3 (Q{beta}MSP3) and UB05 (Q{beta}UB05) in individuals living in two areas of Cameroon differing in transmission intensity. We observed differences in antigen specific IgG and IgG subclass responses which was dependent upon the antigen type, malaria transmission intensity, HIV infection, malaria infection and dual HIV-malaria infections. Individuals living in high malaria transmission areas irrespective of HIV or malaria status had significantly higher IgG responses to both antigens (P=0.0001 for Q{beta}MSP3, P=0.0001 for Q{beta}UB05) than their counterpart from low transmission areas. When dual HIV-Malaria infection is considered significantly higher Q{beta}MSP3 specific IgG1 (P=0.0001) and IgG3 (P=0.04) responses in double negative individuals was associated with protection against malaria in low transmission areas. Superior Q{beta}UBO5 specific IgG1 responses (P=0.0001) in double negative individuals were associated with protection in high transmission areas in contrast to significantly higher IgG3 responses to Q{beta}UB05 (P=0.0001) which were more relevant to protection in low malaria transmission areas in the same population. Thus, understanding immune responses to Q{beta}UB05 and Q{beta}MSP3 could facilitate the development of immunotherapeutic strategies suitable for areas differing in malaria transmission intensity.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Lissom, A., Ouambo, H. F., Megnekou, R., Okeke, M. I., Ngu, L. L., Netongo, P. M., Ngoh, A. A., Sanders, C. A., Bawage, S., Tchouangueu, T. F., Tchadji, C. J., Okoli, A. S., Njambe Priso, G. D., Garcia, R., Gutierrez, A., Chukwuma, G. O., Esimone, C. O., Achidi, E. A., Mbacham, W. F., Kaptue, L., Leke, R. F., Park, C. G., Bopda Waffo, A., Nchinda, G.. 2018-04-18. Comparative analysis of IgG Responses to recombinant Qβ phage displayed MSP3 and UB05 in Dual HIV-malaria infected adults living in areas differing in Malaria transmission intensities. https://doi.org/10.1101/303628

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

CD19-CAR T-cell therapy resets the EBV+ autoreactive B cell repertoire in autoimmune disease

Epstein-Barr virus (EBV) reprograms autoreactive B cells into activated antigen-presenting cells that drive pathogenic T- and B-cell responses in autoimmune disease. Using EBV B-cell sequencing (EBV-seq), we profiled EBV+ B cells in patients treated with CD19 chimeric antigen receptor (CAR) T cells (systemic lupus, n=6; idiopathic inflammatory myopathies, n=3; systemic sclerosis, n=3) or rituximab (n=15). CAR T cells, but not rituximab, depleted EBV+ B cells, resetting the repertoire toward a naive state: predominantly IgM+ with minimal somatic hypermutation. Post-rituximab B-cells remained class-switched, hypermutated, and activated. Monoclonal antibodies cloned from EBV+ B cells lost autoreactivity after CAR T cells but not rituximab. Sustained drug-free remission occurred in 8/12 CAR-treated but 0/15 rituximab-treated patients. EBV+ B cells were predominantly Latency III and resisted anti-CD20 and anti-CD19 antibodies, yet were killed by CAR T cells and T-cell engagers. CD19-CAR T-cell therapy resets the autoreactive EBV+ B-cell repertoire, which may underlie sustained drug-free remission.

immunology↗

A minimal two-residue C-terminal truncation of AID in adult-onset hyper-IgM syndrome type 2 (HIGM2)

Activation-induced cytidine deaminase (AID), encoded by AICDA, facilitates class-switch recombination (CSR) and somatic hypermutation (SHM) in activated B cells. Loss of AID function causes hyper-IgM syndrome type 2 (HIGM2). While typically autosomal recessive, three C-terminal truncation variants have been reported to act in autosomal dominant manner. We describe a novel heterozygous AICDA nonsense variant, c.589G>T (p.G197*), that truncates the final two C-terminal residues of AID and results in adult-onset HIGM2. Single-cell sequencing of primary patient B cells revealed a complete block in CSR and a [~]10-fold reduction in SHM. AICDA mRNA expression was balanced between wild-type and variant alleles, yet AID protein abundance was reduced to [~]56% with normal subcellular localization. Remarkably, inducible germinal center (iGB) cultures restored CSR in purified naive patient B cells. CRISPR-Cas9 editing of healthy donor B cells confirmed that the iGB platform can rescue B cells harboring heterozygous, but not homozygous, AICDA variants. These results demonstrate that even a two-amino-acid truncation at the AID C-terminus is sufficient to disrupt its function and cause HIGM2.

immunology↗

Defining the Functional Consequence of the Human Ocular Microbiome

The ocular surface is one of the body's most environmentally exposed mucosal barriers, yet it is considered low biomass and harbors orders of magnitude fewer bacteria than microbe-rich sites like the gut. This has cast doubt on whether a functional core ocular microbiome exists at all. Having previously defined a protective gd T cell and IL-17 axis engaged by the murine commensal Corynebacterium mastitidis, we asked whether human-derived bacteria could do the same. Pairing sequencing and culturomics of healthy human conjunctiva from two geographically distinct cohorts, we define a stable core microbiome and identify Corynebacterium bovis as a consistent eye-resident commensal rather than a transient contaminant. In humans, C. bovis elicits a non-pathogenic response marked by IL-17 secretion by {gamma}{delta} T cells and circulating C. bovis-specific IgG, which suggests commensalism rather than pathology. Colonizing mice with human C. bovis strains from Pittsburgh or Miami reproduced this program and conferred protection against ocular infection with Staphylococcus aureus. Together, these findings identify C. bovis as a human-derived ocular commensal that can drive protective {gamma}{delta} T cell immunity, translating a mechanism previously defined only in mice into human relevance and a rational target against sight-threatening infection.

immunology↗